Emerging Use of an Allosteric TKI: Asciminib for the Treatment of Chronic Myeloid Leukemia

Introduction

Chronic myeloid leukemia (CML) is characterized by the translocation between chromosomes 9 and 22 resulting in the Philadelphia chromosome (Ph+)—the BCR-ABL1 fusion protein. It accounts for 15% of adult leukemias and primarily affects older adults, making tolerable treatment options of the utmost importance.¹

The advent of adenosine triphosphate (ATP)–competitive inhibitors that selectively block the activity of the abnormal tyrosine kinase dramatically improved outcomes for patients with CML. These agents include imatinib (Gleevec; Novartis), bosutinib (Bosulif; Pfizer Inc), dasatinib (Sprycel; Bristol Myers Squibb), nilotinib (Tasigna; Novartis), and ponatinib (Iclusig; Takeda Pharmaceutical Company). Despite the revolutionary impact of these tyrosine kinase inhibitors (TKIs) in improving cytogenetic and molecular response rates, several challenges persist. In some cases, a small subset of patients progress to more advanced-phase disease, which is associated with a poorer prognosis. Further, numerous mutations can limit which TKI may be utilized.

Specifically, the T315I mutation presents challenges; only one of the ATP-competitive inhibitors, ponatinib, is efficacious against this mutation. However, the agent is associated with significant adverse effects (AEs), including cardiovascular events such as venous thromboembolic events, arterial occlusive events, heart failure, and cardiac arrhythmias. Tolerability is a major consideration in treating patients with CML, as TKI therapy is often long term and, for more than half of patients, may be required for life to maintain remission.² Each agent has a unique AE profile, which must be considered when selecting an agent for each patient.

Asciminib (Scemblix; Novartis) is a first-in-class small molecule allosteric inhibitor specifically targeting the ABL myristoyl pocket. Prior TKIs target the ATP-binding site of BCR-ABL1, acting as ATP mimetics and thereby blocking ATP from binding to ABL1 kinase. This prevents the conformational changes needed for downstream signaling, restricting the activation of the BCR-ABL1 fusion oncoprotein. Asciminib, rather than binding to the ATP-binding site, binds allosterically to the myristoyl pocket site of the ABL1 kinase. This site is normally occupied by a myristoylated N-terminal that serves to downregulate the ABL1 kinase. However, with the BCR-ABL1 fusion, this autoinhibitory mechanism is lost.

By mimicking myristate’s binding of the myristoyl pocket site, asciminib induces structural change in the BCR-ABL1 oncoprotein and restores inhibition of BCR-ABL1 kinase activity.³ As fewer natural tyrosine kinases contain a myristoyl binding site, the off-target effects and AEs are minimized as compared with preexisting TKI agents.⁴ Based on its unique binding site and associated tolerability profile, asciminib has been extensively studied in recent years.

Asciminib for Patients With Previously Treated CML

The ASCEMBL phase 3, open-label trial (NCT03106779)⁵ randomly assigned 233 patients who had previously received 2 or more prior TKIs to either asciminib or bosutinib. This study found a higher rate of major molecular response (MMR) with asciminib (25.5% vs 13.2% at week 24) and lower rates of gastrointestinal events and laboratory abnormalities.⁶ Notably, evaluation of health-related quality of life (HRQOL) in the ASCEMBL study found general improvement with asciminib for HRQOL and a clinically meaningful increase in diarrhea with bosutinib.⁷ Further, after approximately 4 years of follow-up, fewer patients receiving asciminib discontinued treatment due to AEs (8.3% vs 27.6%), highlighting its long-term tolerability.⁸ Based on this study, asciminib has been approved to treat patients with CML who have previously received 2 or more prior therapies.⁹

Further, 48 heavily pretreated patients with the T315I mutation were given asciminib 200 mg twice daily in the CABL001X2101 (NCT02081378)¹⁰ phase 1, open-label, single-arm trial, which reported 49% achieved MMR. These results led to asciminib’s approval for treatment of patients with T315I-mutated CML in chronic phase.¹¹

Asciminib as a Frontline Agent

Notably, recent evidence has supported the use of asciminib in the frontline setting, as demonstrated by the ASC4FIRST (NCT04971226)¹² and ASCEND trials (ACTRN12620000851965).^4,13,14

The ASC4FIRST trial was a phase 3, multicenter, open-label study that randomly assigned 405 adults with newly diagnosed CML to either asciminib 80 mg once daily or to an investigator-selected TKI (imatinib, bosutinib, dasatinib, or nilotinib). Subjects were stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by prerandomization TKI selection (first- [imatinib] vs second-generation agent). The primary outcome was major molecular response (MMR) at week 48 for asciminib vs imatinib and for asciminib vs all the TKIs together. Secondary end points were MMR at week 48 for asciminib vs second-generation TKIs, as well as safety reporting.¹⁴

After a median follow-up of approximately 16 months, at week 48, 67.7% of patients achieved an MMR in the asciminib group compared with 49% of patients in the investigator-selected TKI group (difference, 18.9%; 95% CI, 9.6%-28.2%; adjusted 2-sided P < .001). Within the imatinib stratum, 69.3% of patients receiving asciminib had an MMR at week vs 40.2% of patients in the imatinib group (difference, 29.6%; 95% CI, 16.9%-42.2%; adjusted 2-sided P < .001). Within the second-generation TKI stratum, MMR at week 48 was 66.0% for patients receiving asciminib and 57.8% for patients receiving second-generation TKI (difference, 8.2%; 95% CI, −5.1% to 21.5%).¹⁴

With respect to safety end points, the incidence of grade 3 or higher AEs leading to discontinuation was less frequent for patients receiving asciminib compared with either imatinib or the second-generation TKIs. Specifically, grade 3 or higher AEs occurred in 38%, 44.4%, and 54.9%, respectively, while AEs leading to discontinuation occurred in 4.5%, 11.1%, and 9.8%, respectively.¹⁴

The ASCEND trial by the Australasian Leukaemia and Lymphoma Group administered asciminib to patients with newly diagnosed CML and found that after a median follow-up of 21 months, 93% of the 101 patients achieved early molecular response (BCR-ABL ≤ 10% at 3 months) and an MMR rate at 12 months of 79%. Tolerability was achieved with 6% of patients withdrawing due to AEs.⁴

Dosing and Administration

Asciminib dosing varies depending on the specific indication.¹⁵ For patients with CML without the T315I mutation, asciminib can be prescribed as 80 mg once daily or 40 mg twice daily. Interim results from the phase 3 AIM4CML study (NCT04666259)¹⁶ reported comparable safety with once- vs twice-daily dosing.¹⁷ For patients with the T315I mutation, the dose of asciminib is 200 mg twice daily. Doses may be reduced for AEs, such as myelosuppression, elevations in amylase or lipase levels, or grade 3 or higher AEs. Notably, patients should be instructed to avoid food for at least 2 hours before and 1 hour after asciminib. The tablets must be swallowed whole and not broken, crushed, or chewed.

AEs and Monitoring

Overall, product labeling lists the most common AEs as musculoskeletal pain, rash, fatigue, upper respiratory tract infection, headache, abdominal pain, and diarrhea. The most common grade 3 or higher AE reports are myelosuppression and alterations in laboratory values such as calcium, amylase and lipase, cholesterol, uric acid, liver enzymes, and triglycerides.¹⁵

Real-world evidence reporting suggests that the most frequent AEs are fatigue, thrombocytopenia, anemia, and arthralgias. Further, toxicities associated with other TKIs, such as diarrhea, cardiovascular events, edema, and pleural/pericardial effusions, occurred less frequently with asciminib. Cross-toxicity risk was highest for thrombocytopenia, anemia, neutropenia, fatigue, nausea, and pancreatitis.¹⁷ Similarly, a recent systematic review found thrombocytopenia to be the most common AE, reported in 22.5% of patients receiving asciminib.¹⁸

The ASC4FIRST study compared asciminib with other frontline TKIs, finding superiority for asciminib with respect to safety and tolerability. Specifically, there were lower rates and durations of diarrhea, anemia, and lipase elevation when compared with second-generation TKIs but not when compared with imatinib. Further, rates of dose reduction, interruption, or discontinuation were lowest with asciminib.¹⁹

In addition to monitoring for AEs, patients receiving asciminib should be monitored according to current guidelines for response.² Thus, patients should be educated on the importance of medication adherence and laboratory monitoring to ensure attainment of optimal response at specified time points.²⁰ Notably, while asciminib can be used to treat T315I mutations, there are still a number of BCR-ABL1 kinase domain mutations/variants that can confer resistance to asciminib. Therefore, inadequate response to asciminib treatment should prompt kinase domain mutation testing.²

Discussion

In October 2024, the FDA granted accelerated approval to asciminib for adult patients with newly diagnosed Ph+ CML in chronic phase based on the results of ASC4FIRST.²¹ Updated guidelines from the National Comprehensive Cancer Network now offer asciminib as a frontline agent alongside the first- and second-generation TKIs, all with a category 1 recommendation for patients with any risk prognostic score. Further, the guidelines preferentially recommend a second-generation agent or asciminib for patients with intermediate- or high-risk prognostic scores due to the lower risk of disease progression as compared with imatinib.² Data show a generally quicker time to cytogenetic and molecular response, less progression to advanced phases, and improved tolerability. Asciminib is likely to be utilized more frequently in practice after attaining a recommendation in both frontline and subsequent lines of therapy. Notably, asciminib is currently available from 2 specialty pharmacies, Biologics by McKesson and Onco360.

Future Directions

Although much progress has been made in the management of patients with CML, further optimization of dosing to minimize AEs while maximizing efficacy to permit a potential treatment-free remission is crucial. A paucity of data exists for use of asciminib in the posttransplant setting, in patients with myristoyl pocket mutations, and in patients younger than 18 years. Therefore, ongoing studies of asciminib are evaluating dose optimization, utility in pediatric patients, and possible combination regimens.²²

Conclusions

Increasing evidence supports the use of asciminib in the frontline treatment of CML given improved outcomes and high rates of tolerability. Providers should evaluate patient-specific characteristics when selecting an agent for each individual patient.

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